20-41202162-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384317.1(ZHX3):ā€‹c.2755A>Gā€‹(p.Thr919Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000843 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00011 ( 0 hom., cov: 32)
Exomes š‘“: 0.000081 ( 0 hom. )

Consequence

ZHX3
NM_001384317.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.109
Variant links:
Genes affected
ZHX3 (HGNC:15935): (zinc fingers and homeoboxes 3) This gene encodes a member of the zinc fingers and homeoboxes (ZHX) gene family. The encoded protein contains two C2H2-type zinc fingers and five homeodomains and forms a dimer with itself or with zinc fingers and homeoboxes family member 1. In the nucleus, the dimerized protein interacts with the A subunit of the ubiquitous transcription factor nuclear factor-Y and may function as a transcriptional repressor. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0048797727).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZHX3NM_001384317.1 linkc.2755A>G p.Thr919Ala missense_variant Exon 3 of 4 ENST00000683867.1 NP_001371246.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZHX3ENST00000683867.1 linkc.2755A>G p.Thr919Ala missense_variant Exon 3 of 4 NM_001384317.1 ENSP00000506788.1 Q9H4I2-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152094
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
41
AN:
251358
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135834
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00162
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.0000814
AC:
119
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.0000715
AC XY:
52
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00144
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.000175
AC XY:
13
AN XY:
74410
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00132
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 919 of the ZHX3 protein (p.Thr919Ala). This variant is present in population databases (rs748783597, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ZHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1402056). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
1.9
DANN
Benign
0.24
DEOGEN2
Benign
0.0055
T;T;T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.53
.;.;.;T
M_CAP
Benign
0.0030
T
MetaRNN
Benign
0.0049
T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.48
N;N;N;N
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.59
.;N;N;.
REVEL
Benign
0.024
Sift
Benign
1.0
.;T;T;.
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0
B;B;B;B
Vest4
0.035
MutPred
0.18
Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);
MVP
0.19
MPC
0.23
ClinPred
0.013
T
GERP RS
-1.9
Varity_R
0.038
gMVP
0.076

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748783597; hg19: chr20-39830802; API